Arsenical solutions and method of preparing same



Patented Mar. 15, 1927.

OTTO LOWY, 0F NEWARK, NEW JERSEY STENECK TRUST COMPANY, TRUSTEE CORPORATION OF NEW JERSEY.

ARSENICAL SOLUTIONS AN D No Drawing. Application filed December 'My present invention relates to the preparation'of solutions of arsenical compounds, partlcularly solutions of arsphenamine suitable for intravenous iniection. It is an ob- 5 ject of the present invention to provide an 10 form of the (ii-sodium salt of arsphenamine,

are obtained, which may readily and safely be administered, and which shall, by reason of certain peculiar and valuable properties possessed by them as a result, in part at least, of the modeof their preparation, largely eliminate a whole class of undesirable and often fatal resultsgenerally following the use of arsenical preparations, particularly solutions of arsphenamine such as the di-sodium salt of arsphenamine, as hitherto prepared and administered.

By way of example I shall, in the accompanying specification, describe in detail illustrative embodiments of the process and product of my invention, itbeing, however, understood, that my invention is not limited to such illustrative embodiments which are herein set forth for'purposes of illustration only.

' Referring more particularly to the illustrative embodiments of my invention here in set forth, it is to be noted that in the procedure hitherto followed in the preparation of arsenical solutions, particularly solutions of. arsplienamine, such as the di-sodium salt of arsphenamine, for their administration by hypodermic injection, it has been customary, taking arsphenamine for eX- ample, to prepare a solution of this substance by dissolving the same in an aqueous solution and neutralizing or alkalinizing by'the use of an aqueous solution of a caustic alkali, such as sodium hydroxide. The directions usually given require that the caustic alkali be added so as to be in slight excess, this slight excess being considered in the art clear indicationof the complete neutralizing of the acid molecules of the arsphenamine, and the complete conversion of the same into the di-sodium salt. This mode of procedure is characterized by four phases: In phase A we have arsphenamine as yet unconverted and consisting of the di-hydrochloride of diamino-dioxy-arseno-benzol. This is read- ASSIGNOR, BY MESNE assrenmniirs mo orfnononnlw NEW JERSEY, A BA KING METHOD or PREIF'ARING SAME.

1920. Serial No. 432,081.

ily soluble in water. Phase B is character ized by the temporar precipitationof the base ot arsphenamine, namely, diaminodioXy-arseno-benzol, which is insoluble in water, by the addition of a comparatively small amount of the aqueous solution of caustic soda. Phase C is characterized by the conversion of the arsphenamine base into the mono-sodium salt of arsphenamine by the addition of a greater 'amount of aqueous solution of caustic soda than is necessary to precipitate-the base, but less than the amount necessary to produce the di-sodium salt. 7 In this phase of the reaction, the monosodium salt exists probably in the condition of a colloidal suspension in the solvent, the 1nono-sodiumsalt not being readily soluble in water.- acterized by the production ofthe di-sodium salt of arsphenamine by the addition of a still further quantity of the aqueous solution of caustic soda in excess of what isre quired to produce the mono-sodium salt, and, as is generally recommended slightly in excess of what would ordinarily be requiredito convert the arsphena-mine into the di-sodium' salt. This analysis of'the reaction applies also to tion described and claimed in my co-pending application, Serial N 0. 432,082 filed Decenr her 2( 1920, which solution is characterized by being substantially gasfree, and particularly free from oxygen and containing an the improved form of arsenical solu PhaseD is charexcess of alkali, generally amounting to' from about-one-third to aboutfour gram-' molecules of caustic alkali per gram-mole cule of the di-sodium salt of arsphenamine' I have discovered that there is "anadditional phase in the reaction analyzed above, which has hitherto not been suspected, and the failure to account for which has resulted in an inferior solution, the use of which is fraught with dangerous and often fa tal results. I have discovered that as intermediate phases G and D, defined above, there is a further phase which may be called phase C-D, during which, even though there may be present in the solution enough caustic soda or other caustic alkalito bring about the complete conversionof the ars phenamine into the (ii-sodium salt, or even a considerable excess of caustic alkali over what 1s requlred to bring about such a converslon, a substantlal amount of 'the monosalt in-the .tion in this condition dangerous, often following its administration closely analogous to the vsymptoms.fQlloW- ing the existence of an 'embolus in the cirsodiurn salt ;formed; during the intermediate reaction remains undissolved, and remains suspended as a colloid in the solution. The resenceof this unconverted mono-sodium form of an insoluble colloid 'renders theadministration of the arsenical solusymptoms. Whichare ulaterytsys mxot he p tient.- Where the dos f rsenical. so tio containing a n-1 sidenable amount of the ,nndissolved monosodiu I salt; is; I considerable, the patient" to Whom thesolution is administered sufiers an ex tr Inely unfayorable, reaction, and often I j hayefu rther.; discpyered that if the ar-.

sen eal solution;as;the;;solution of arsphenamin h 0f the di-sodium Salt; of arsphena nin :deseribedlabove, is permitted.toage,

that s, .-if. a necessary time factor is taken i iii eonsiderationinthe pre-parat onbf the arsenicalsolu tion,-,-prior to, its

,tion, 1 the, conversion 1 of the arsphenamine into the Edi-sodium salt will become ,coinplete by the complete eliminationof the mono-so- Y dium, salt by itsiconversion into. thedi-sodiuin oxidizing-agents, the .arsenical solution will, tho ggh-' free. from the undissolved 1non o-s0-.

' 40 diuin salt become so. t'oxic,,by.reason of the thesame wholly unfit for i use. a

sal Ur der i ordinaryconditions this aging period, which; may readily be determined bytrialand experiment and I by, a microscopic on ,of 1 the resulting solution, is ap pronnnat ly' equal; a four I hours.

. I glld-YQ f rr'ther;discovered :thatwif the aging of the arsenicalsolution, in accordance Witlrsthe fo regoing lprocedure, is permitted to take place in the presence. of ainor other .exana nati as to render oxidationof the ,arsphenamine,

I have, however fonndthat if the aging.,is'conducted 7 i? t ew-Pre ent the;solntion of-sa d eo-pending application: 55

unders non-oxidizing conditions, asnnder a vacuum on Sunder-an inert; gas, .the; final. solutionravill have alL the qlesirable properties of; ;a gas-,frega, unoxidized {solution of the. di-

sodinnrsalt Substantially free from the undesirable mono-sodiumsalt. In particular, if I treattthesolution prepared: in accordance -gvith any ,cO-pending, application re,-

, according to etherprocedure nventiomthflti is, if I permit ferred to above to age: for; about foumhours, before administering the same l obtain; a solution which, while non-toxic ,andfree. from gas and oxidizedg co nponents, ,isalso -free; from y the undesirable, undissolved monoqsodium salt. The result-ingsolution is of a degreeof alkalin'ity-v-correspondingto about one-third to about four gramrinolecules of caustic alkali to a gnanymolecule; of; 1 arsphenamine; This corresponds to; an; addition; to: the di-hyfdrochloride of from about four and one-third administrw to about eight 1, gram-molecules of; caustic soda to a gramanolecule of di-hydrochloride. The solution is prepared under nonoxidizing conditions, asby being prepared undera vacuum, or under an inert gas, such as nitrogen. Theaging may take'place un- .der similar conditionsbefore sealing in an While this conversion agent, as already set forth above, IGSLll'ESdH theoxidation of the arsenical compound and consequently in the increased toxicity of such compound to the point often=of.re11 der.-. ingthesame totally unfit! for use. I have further.discovered that here theamount of free-alkali present in the solution above the quantity necessary toproduce the .di-soe dium salt is considerably in iBXCfiSSOf. such quantity,-the conversion .of the. monoeso dium into the .di-sodium' salt complete. may be readily controlle'd byz'trial and eX-. periment, especially since within the .limits of free alkali specified in this specification isapparently less: This, however, is a feature. wh ch the 'conver-sionis completefiand tlre iultimate solution free from any undesirable properin this'speoi-ficar ties of the kind discussed tion. V i It is of course to be understood--thatmy invention is notto be limited;to-thepa1i ticular embodimentspurposes of illustratioi'i only.

lVhatI claim is;:; V V V 1. The method which comprises adding, to

an1arseno benzol;derivative an.-.amount of caustic alkali at leastsuflicient'toi-convert an arseno-benzol derivative into 'a solutionaof. the di-alkah salt, and. thereafter permitting the resultingsolutionto age in. 1the.absence of oxygen for a length of-time suflicient-to cause the reactionresultingin-the formation ofthe di-alkali. salt to become complete. 2. The method Whichcomprises adding to an arseno-benzol derivative -under oxygen.- free conditions an amount OfCfltlStl-Cfilkfil'latleast suflicienttotconvert an .arseno-ibenr. ZOl derivative .intoxa solution. of. the-dialkali salt, and. thereafter permitting ,the aresulting solution .to. age, in the absence of city: gen for; a length of time sufiicient to cause herein set forth for themeaction resulting inthe formation of v the di-alkalisalt to becomecompletes,

3. The-method yhichicomprises' adding. to arseno-benzol derivative caustic soda substantially in excess of theamount required to convert the arseno-benzol derivative into a solution of the di-sodium salt, and thereafter permitting the resulting solution to age in the absence of oxygen for a length of time formation of the disodium salt to become complete. 7

5. The method which comprises adding to the (ii-hydrochloride of diamino-dioxy-arseno-benzol an amount of caustic alkali at least sufficient to convert said di-hydrochloride into a solution of the di-alkali salt, and thereafter permitting the resulting solution to age under non-oxidizing conditions for a length of time sufficient to permit a conversion of substantially all of the mono-alkali salt formed as an intermediate product of the reaction into di-alkali salt.

6. The method which comprises adding to the di-hydrochloride of diamino-dioxy-arseno-benzol under non-oxidizing conditions an amount of caustic alkali at least sufficient to convert said di-hydrochloride into a solution of the di-alkali salt, and thereafter permitting the resulting solution to'age under nonoxidizing conditions for a length of time sufficient to permit a conversion of substantially all of the mono-alkali salt formed as an intermediate product of the reaction int-o the di-alkali salt. 7 1

7. The method which comprises adding to the (ii-hydrochloride of diamino-dioxy-arseno-benzol from about four and one-third to about eight gram-molecules of caustic soda, being an amount of caustic alkali substantially in excess of the amount required to convert said di-hydrochloride into a solution of the di-sodium salt, and thereafter permitting the resulting solution to age under non-oxidizing conditions for a length of time sufficient to permit a conversion of substantially all of themono-sodium salt formed as an intermediate product of the reaction into di-sodium salt.

8. The method which comprises adding to the di-hydrochloride of diamino-dioxy-arseno-benzol under non-oxidizing conditions from about four and one-third to about eight gram-molecules of caustic soda, being an amount of caustic alkali substantially in excess of the amount required to convert said di-hydrochloride into a solution of the disodium salt, and thereafter permitting the resulting solution to age undernon-oxidizing conditions for a length of time sufficient to. permit a conversion of substantially all of the mono-sodium salt formed as an'intermediate product of the reaction into the disodium salt. p 9. The method of manufacturing a prophylactic compound which comprises adding to arsphenamine an amount of caustic alkali at least suflicient tov convert the arsphenamine into a solution of the di-alkali salt, and closing said solution in an ampule under non-oxidizing conditions. 10. The method of manufacturing 'afprophylactic compound which comprises adding to arsphenamine an amount of caustic alkali at least sufficient to convert the arsphenamine into a solution of the di-alkali.

salt, and sealing the same in an ampule'in I the presence of nitrogen.

llpThe method of manufacturing av prophylactic which comprises adding to ars phenamine under oxygen-free conditions, an amount of caustic alkali at least suiiicient to convert the arsphenamine into a solution of the di-alkali salt, and closing said solution in an ampule under non-oxidizing conditions.

12. The method of manufacturing a prophylactic which comprises adding toarsphenamine under oxygen-free conditions, an

amount of caustic alkali at least sufficient to convert the arsphenamine into a-solution of the di-alkali salt, and sealing the same in an ampule in the presence of nitrogen.

13. The method which comprises adding to the di-hydrochloride hydroxy-arseno-benzol an amount of caustic alkali at least sufiicient to convert said dihydrochloride into a solution of di-alkali salt, sealing said solution in an ampule under non-oxidizing conditions, and permitting the same to age until all of the mono-alkali of diamino-di-.

salt formed as an intermediate product is.

converted into the di-alkali salt.

14'. The method which comprises, adding to the di-liydrochloride of diamino-dihydroxy-arseno-benzol an amount of caustic alkali at least sufficient to convert said dihydrochloride into a solution of di-alkali salt, sealing said solution in an ampule in the presence of inert gas, and permitting the same to age untilall of the mono-alkali salt formed as an intermediate product is converted into the di-alkali salt.

15. The method which comprises adding to the dl-hydrochloride of diamino-dihydroXy-arseno-benzol an amount of caustic alkali at least sufficient to convert said dihydrochloride into a solution of ,di-alkali salt, sealing said solution in an ampule in the presence of nitrogen, and permitting the same to age until all of the mono-alkali salt formed as an intermediate product is converted into the di-alkali salt.

' 16."The"'1netliod' which compris s adding toI-the di hydrochloride of diamino-dihy- I pii'le" tuitilTall of" the mono-sodium salt: formed as an intermediate product of the" 10 the di-Sodit'nn'salt.

drexymeant-helmet from" about four and one-third to about eight gram-'inolecules'ot catnstie"s0d%i, se2t1ing the resnltlng'solut on' in an ampnle in the presence of inertega s, and permlttlng the same to age in saad amrezictio'n is'converted into 17. Themelthod which comprises adding 10 the di y fhlb of fl droxy-arseno-b'enzol from about four and on'e-'third'to about eight; grain-molecules of c'ziti'stidso dfij sealing the ie'sti in an ampnle 1n the presence of mtrog'emand pe'fii'iftting'the"same to" age 111 said ampule an intefniediz'tte"prodtict of the reziction' is converted into the di sodiiiin salt;

18'. The m'e'tl iot Wl 'ich compfises 7 adding he dihy' armymrsemben o1 under 1 lting solution fthe mono-sodium salt formed 21's;

conditions 'fro111'eboutf0ur and one-third to ahout 'e1ght gram-molecules of causticT soda, seahn'gthe resultlng solution 111' an ampule under non-oxidizing conditions, and permitting'the same 1nono'-sod1un1 salt formed as an intermediate product of the reaction is converted into the d i-sodium salt.

to age until all of the 19$The method which comprises addiiig in the presence of nitrogen, and permitting the'saine to age tintil all of the mono-sodium salt formedasan' intermediate product of; the reaction is converted'intoithe di-SOCilUnT salt.

In testimony Wh'e'reofjI have signed m name to this specification this 17th day of December, 1920. i OTTO LOVVYL 

